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Toll‐like receptor‐mediated IRE1α activation as a therapeutic target for inflammatory arthritis

Quan Qiu, Ze Zheng, Lin Chang, Yuan‐Si Zhao, Can Tan, Aditya Dandekar, Zheng Zhang, Zhenghong Lin, Ming Gui, Xiu Li, Tongshuai Zhang, Qingfei Kong, Hulun Li, Sha Chen, An Chen, Randal J Kaufman, Wei‐Lei Yang, Hui‐Kuan Lin, Donna Zhang, Harris Perlman, Edward Thorp, Kezhong Zhang, Deyu Fang

Author Affiliations

  1. Quan Qiu1,
  2. Ze Zheng2,
  3. Lin Chang3,
  4. Yuan‐Si Zhao4,
  5. Can Tan1,
  6. Aditya Dandekar5,
  7. Zheng Zhang6,
  8. Zhenghong Lin1,
  9. Ming Gui1,
  10. Xiu Li7,
  11. Tongshuai Zhang7,
  12. Qingfei Kong1,7,
  13. Hulun Li7,
  14. Sha Chen8,
  15. An Chen8,
  16. Randal J Kaufman9,
  17. Wei‐Lei Yang10,
  18. Hui‐Kuan Lin10,
  19. Donna Zhang11,
  20. Harris Perlman12,
  21. Edward Thorp1,
  22. Kezhong Zhang*,2,5 and
  23. Deyu Fang*,1,6
  1. 1 Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  2. 2 Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA
  3. 3 Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI, USA
  4. 4 Department of Surgery, Jimo Hospital of Chinese Traditional Medicine, Qingdao, China
  5. 5 Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI, USA
  6. 6 Department of Surgery, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  7. 7 Heilongjiang Provincial Key Laboratory of Neurobiology, Department of Neurobiology, Harbin Medical University, Harbin, China
  8. 8 Department of Clinical Biochemistry, Third Military Medical University, Chongqing, PR China
  9. 9 Neuroscience, Aging, and Stem Cell Research Center, Sanford‐Burnham Medical Research Institute, La Jolla, CA, USA
  10. 10 Department of Molecular and Cellular Oncology, MD Anderson Cancer Center, The University of Texas, Houston, TX, USA
  11. 11 Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA
  12. 12 Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  1. *Corresponding authors. Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA. Tel.:+1 313 577 2669; Fax:+1 313 577 5326; E-mail: kzhang{at}med.wayne.eduDepartment of Pathology, Northwestern University, 303 East Chicago Avenue, Chicago, IL 60611, USA. Tel.:+1 312 503 3021; Fax:+1 312 503 3023; E-mail: fangd{at}northwestern.edu

Abstract

In rheumatoid arthritis (RA), macrophage is one of the major sources of inflammatory mediators. Macrophages produce inflammatory cytokines through toll‐like receptor (TLR)‐mediated signalling during RA. Herein, we studied macrophages from the synovial fluid of RA patients and observed a significant increase in activation of inositol‐requiring enzyme 1α (IRE1α), a primary unfolded protein response (UPR) transducer. Myeloid‐specific deletion of the IRE1α gene protected mice from inflammatory arthritis, and treatment with the IRE1α‐specific inhibitor 4U8C attenuated joint inflammation in mice. IRE1α was required for optimal production of pro‐inflammatory cytokines as evidenced by impaired TLR‐induced cytokine production in IRE1α‐null macrophages and neutrophils. Further analyses demonstrated that tumour necrosis factor (TNF) receptor‐associated factor 6 (TRAF6) plays a key role in TLR‐mediated IRE1α activation by catalysing IRE1α ubiquitination and blocking the recruitment of protein phosphatase 2A (PP2A), a phosphatase that inhibits IRE1α phosphorylation. In summary, we discovered a novel regulatory axis through TRAF6‐mediated IRE1α ubiquitination in regulating TLR‐induced IRE1α activation in pro‐inflammatory cytokine production, and demonstrated that IRE1α is a potential therapeutic target for inflammatory arthritis.

  • Received November 20, 2012.
  • Accepted July 15, 2013.

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